Throughout this application various publications are referred to in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications, and all patents, patent application publications and books referred to herein, are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Glioblastoma Multiforme (GBM) is the most malignant and lethal form of astrocytoma (WHO grade IV). Despite recent advancements in the standards of care, the outlook for GBM patients remains bleak and new therapies are therefore swiftly required. Currently, the standard of care is gross tumor resection followed by radiation treatment and concurrent chemotherapy. However, even after extensive therapy, relapse is certain and the disease remains lethal (1).
Microglia are the resident macrophages of the central nervous system (CNS) (2, 3). They are glial cells that are of hematopoietic origin. Microglia are the main phagocytic and immunocompetent cells in the CNS. They are activated by damage or infection and phagocytose debris and other cells. They also present antigens and secrete cytokines that regulate inflammatory responses. Microglia are attracted by glial tumors via multiple tumor-secreted factors and are enriched in the tumor periphery (4, 5). The extent of microglia infiltration correlates with tumor grade (6, 7). In glioblastoma, microglia account for as much as 30% of the tumor mass (8). Instead of producing an anti-tumor effect, microglia are co-opted by the tumor to favor its growth (4, 5). In this reprogrammed state, they support the tumor by secreting factors that promote immunosuppression, and glioblastoma cell proliferation, invasion and angiogenesis. Importantly, selective ablation of microglia has been shown to inhibit glioblastoma invasiveness and growth (9, 10).
Additionally, solid tumors in general are also a challenge to treat with non-surgical means. Additionally, solid tumors in general are also a challenge to treat with non-surgical means. Novel methods to treat solid tumors are urgently needed. Importantly, macrophages are thought to be necessary for the malignant behavior of many, if not most, solid tumors, including Ewing's sarcoma (De Palma M, Lewis C E: Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013, 23:277-286/Fujiwara T et al: Macrophage Infiltration Predicts a Poor Prognosis for Human Ewing Sarcoma. Am J Pathol 2011, 179:1157-1170).
The present invention addresses the need for improved astrocytoma treatments, including for glioblastomas, and new methods for treating solid tumors, including Ewing's sarcoma.